Process for the preparation of 1,2-benzisothiazolin 3-ones

ABSTRACT

The process disclosed herein involves the cyclization of benzene sulfenamides and derivatives thereof to produce 1,2benzisothiazolin-3-ones in accordance with the following reaction:   WHEREIN R is a hydrocarbon or substituted hydrocarbon radical as defined hereinafter, R&#39;&#39; is a hydrocarbon or substituted hydrocarbon radical as defined hereinafter, Y is an inert group, and n is an integer of 0 to 2 in value. The products are useful as bacteriocides and fungicides.

United States Patent [191 Grivas 1 Jan. 28, 1975 PROCESS FOR THE PREPARATION OF 1.2-BENZISOTHIAZOLIN-3-ONES Primary Examiner-Richard J. Gallagher Attorney, Agent, or Firm-Richard G. Smith; Walter J.

[75] Inventor: John C. Grivas, South Holland, lll. Monacem [73] Assignee: The Sherwin-Williams Company,

Cleveland, Ohio [22] Filed: June 2, 1972 [57] ABSTRACT [2]] A N 259,115 The process disclosed herein involves the cyclization I of benzene sulfenamides and derivatives thereof to Related Appllcamm Dam produce l,2-ben2isothiazolin-3-on es in accordance [63] Continuation-impart of Ser. No. 32,467, April 27, with the following reaction:

1970. abandoned.

Q Q C-OR' c Y- NR R'OH n SNHR n .s

[52] U.S. CL... 260/304, 260/2565 R, 260/2948 C, wherein R is a hydrocarbon or substituted hydrocar- 260/470, 424/251, 424/263, 424/270 bon radical as defined hereinafter, R is a hydrocarbon [51] Int. Cl C07d 91/10 or substituted hydrocarbon radical as defined herein- [58] Field of Search 260/304, 256.5 R, 294.8 C after, Y is an inert group, and n is an integer of 0 to 2 in value. The products are useful as bacteriocidcs and [56] References Cited fungicides.

UNITED STATES PATENTS 13 Claims N0 Drawings 3.661.974 5/1972 Grlvas i. 260/304 1 PROCESS FOR THE PREPARATION OF 1 1 .1 35 ESQ HIA QL NQ-Q ES This application is a continuation-in-part of copending application Ser. No. 32,467, filed Apr. 27, 1970 Methods A and B involve a sequence of 5 and 6 steps respectively utilizing the same starting compound (I). This precursor, in turn, is prepared from commercially available methyl anthranilate by diazotization followed now abandoned. 5 by reaction with a sulfur source.

U.S. Pat. No. 3,300,378 teaches the preparation of BACKGROUND OF THE INVENTION Compounds having the formula 1. Field of the Invention This invention relates to a new process for preparing l,2-benzisothiazolin-3-ones. More specifically, it re- 10 lates to an improved process involving the cyclization 8/ of benzene sulfenamides, particularly 2-carboalkoxy- N-substituted benzenesulfenamides.

2. Related Prior Art b y three different methods involving cyclization. How F" f f i ltz'benzlsothlam' ever there is no disclosure therein of compounds havdenvatwes o the a ing a substituent group attached to the nitrogen nor Q that cyclization could be effected if such substituent \N group was on the nitrogen prior to cyclization. Morel over, while Z is defined as including groups capable S of reacting with a hydrogen atom linked to the nitrogen wherein R" is defined as various hydrocarbon groups atom of ammonia," the only P groups and derivatives thereof. As pointed out in this patent, Closed are clllol'me and bromme- There no these compositions are very useful in the control of F thatz mlghtbe an ester p Furithermorel whlle bacterial and fungal growth and also for use in pharma- It Suggested h Z -8 C1 of might effect Y ceutical formulations for human and veterinary medilatlonby l one such g P P with 2 cine, such as for local treatment for athletes foot and there IS mdlcatlon that undlsclosed p, Such ringworm of the scalp, as general or urinary antiseptics, as an g p, Could effect y z i n y reaction etc. with the third or last hydrogen as in -S-NHR, U,$ Pat, N 2,870,015 l i rt i 1,2- 3 where R is a hydrocarbon group or substituted hydrobenzisothiazolinones as stabilizers for photographic silrbon group. ver halide emulsions. These compounds are prepared SUMMARY OF THE INVENTION trom a common precursor, methyl 2-mercaptobenzoate (l), by two general methods as illustrated in Scheme In accordance with the present invention a new prol (L. L. Bambas in The Chemistry of Heterocyclic Cess has been found which gives improved results in the Compounds" Vol. 4, A. Weissberger, Editor, lnterscipreparation of l,2-benzisothiazolin-3-ones. This proence Publishers, lnc., New York, N.Y., 1952, pp. cess involves the cyclization ofcarboalkoxybenzenesul- 253 277) fenamides, preferably N-substituted-ca.rboalkoxyben- SCHEME I 000011 coon HOOC 2 2 steps a SH 1. Hydrolysis S-S I 2. Oxidation II COCl ClOC II S001 s s III 9 III 2 ste s l. Halogenat on 2 2 RNH cyclization IV Method B CONHR v 2 2 (Br; or C1 5 Glacial CONHR RHNOC Acetic Acid 3 4 zenesulfenamides and the like as illustrated by the folboalkoxy (COOR), alkoxy, cycloalkoxy, aryloxy, lowing reaction: hydrocarbon and substituted hydrocarbon radicals of Q 4 g C-OR' 3 n SNHR n 2 NR R OH 6 wherein: no more than 20 and preferably no more than carbon R represents a hydrocarbon radical of not more than N) atoms, and preferably containing no aliphatic unsaturapreferably not more than 8 carbon atoms, intion, the substituentgroups in the substituted hydrocarcluding aliphatic, cycloaliphatic and aromatic hybon radicals being selected from alkoxy, cycloalkoxy, drocarbon groups, saturated or unsaturated in the aryloxy, chloro and bromo groups, each of the halogen aliphatic portions thereof, hydroxy alkyl radicals of atoms being attached to an aromatic nucleus in the hynot more than 8 carbon atoms, halogenated arol5 drocarbon radical, Two Y radicals can represent a dimatic h d b groups i hi h th h l i valent radical which has both valencies attached to the h d to an aromatic l d i id l d benzene nucleus of the formula and thereby forms a pyridyl radicals, the pyrimidyl and pyridyl groups Second cyclic structure such as in naphthalene derivab i h d to h N f h f l h h h tives. Preferably no more than one Y represents a nitro carbon atoms of the respective ring structures; 20 0F carboalkoxy prepresents a hydrocarbon radical of not more than Typical Y radicals include the hydrocarbon radicals 20 and p a y not r than 5 carbon a m listed above for R, the bromo and chloro aromatic hyincludlng aliphatic, cycloallphatlc and aromatic drocarbon groups listed above for R, and also chloro, radicals, the aliphatic portions thereof preferably b h h r b t h xox being Saturated; decoxy, dodecoxy, phenoxy, methylphenoxy, ethyl- Y represents a radical which will remain inert during phenoxy, phenethoxy, benzyloxy, methoxyphenoxy, the reactions used in preparing the compound and methoxynaphthyloxy, diphenyloxy, chlorophenoxy, in subsequent cyclization reactions described bromophenoxy, chloronephthoxy, chlorobenzyloxy, herein, and methoxybenzyloxy, cyclohexyloxy, cycloheptyloxy.

n is an integer having a value of 0 to 2. methylcyclohexyloxy, methylcycloheptyloxy, ethylcy- In the compounds represented by the above formuclohexyloxy, methoxyethoxy, ethoxyethoxy, methoxylas, typical R groups include methyl, ethyl, propyl. buethyl, ethoxyethyl, propoxypropyl, butoxyethyl, and tyl, amyl, hexyl, nonyl, decyl, dodecyl. octadecyl. phethe like.

nyl, tolyl, xylyl, phenethyl. benzyl. naphthyl, diphenyl, The sulfenamides (Formula Xl) used in the present methylnaphthyl, cyclohexyl. cycloheptyl, methylcyinvention are prepared from esters of 2- clohexyl, cyclohexylmethyl. Other groups such as alkemercaptobenzoic acids (Formula V) or their correnyl groups and derivatives of the above hydrocarbon sponding disulfides (Formula Vlll) essentially by a two groups are also suitable for this purpose. However, step reaction as illustrated in the following scheme, since the group is eliminated and discarded eventually wherein X represents Cl r Br Molecular Chlorine or in the cyclization reaction, it is advantageous to use bromine may be used, or the corresponding Sulfuryl simple groups such as methyl, ethyl, etc. halide,

Q l? i? COR' 2 COR R'OC 2 Y Y t Y n SH @:--s s n VII VIII 8013' C OR' as a 2 Y 2\ 2 Y ax 7 n n X SNHP IX XI I Typical R groups include the hydrocarbon radicals When ammonia is used instead of the amine (RNHQ listed above for R and also the following: hydroxyalkyl a disubstituted derivative is obtained as shown hereinradicals, such as methylol, ethylol, propylol, amylol, after in Example X. phenylol, hexylol, octylol, etc., haloaryl such as chloroln practice, neither the disulfides (Vlll) nor the sulphenyl, chlorobenzyl, chloronaphthyl, chlorodiphenyl, fenyl halides (IX) need be isolated. Usually the former bromophenyl, bromobenzyl, bromonaphthyl, iodopheare not very soluble in the reaction solvent (e.g.. CCl nyl, fluorophenyl, chlorophenethyl, etc., Z-pyrimidyl, therefore crystallize out during the operation and can 4-pyrimidyl, 2-pyridyl, 4-pyridyl, allyl, butenyl, styryl, be isolated in high yield and purity. Sulfenyl halides vinylphenyl, cyclohexenyl, propargyl, methoxyethyl, (lX) are ordinarily soluble in the same solvents easily ethoxyethyl, butoxyethyl, propoxypropyl, ethoxyoctyl, forming yellowor red-colored solutions. The isolation cyclohexoxyethyl, phenoxybutyl. ethoxycyclohexyl, of the sulfenamides (Xl can also be avoided. As a matbutoxyphenyl, etc. ter of fact the direct cyclization of sulfenamidcs (XI) The Y radicals include chloro, bromo, nitro, carto the corresponding benzisothiazolin-3-ones is preferred, especially when the latter are liquids and can be isolated by simple distillation. In a preferred reaction sequence, therefore, an ester of 2-mercaptobenzoic acid (Vll) or its disulfide (VIII) is halogenated to form a sulfenyl halide of the structure lX, which is reacted in situ with a primary aliphatic amine to generate a sulfenamide of the structure XI. The latter, in turn, is cyclized in situ to give the desired 1,2-benzisothiazoline- 3-one. This reaction sequence is especially important because the overall operation can be carried out as a continuous process.

The conversion of the sulfenamides to the corresponding benzisothiazolinones is effected in a variety of conditions. When the former are liquids or in highly concentrated solutions, the cyclization takes place very slowly at room temperature. Heating accelerates the reaction, with temperatures of 90200 C. effecting a practical rate of cyclization. For example, N-benzyl-2- carbomethoxybenzenesulfenamide kept at 90 for 22 hours gave Z-benzyl-l,2-benzisothiazolin-3-one in 50% yield. At higher temperatures (100200) certain sulfenamides cyclize in reasonable yields, but slight to substantial decomposition occurs simultaneously. With basic or acidic catalysts a good rate of reaction is obtained at OlOOC.

In contrast, it has been discovered that cyclization takes place at high rates in the presence of catalytic amounts of strong bases, such as metal alkoxides, metal hydroxides or quaternary ammonium hydroxides or alkoxides. The alkoxides are represented by the formula MOR" wherein M represents a quaternary ammonium group or a metal, preferably an alkali metal, and R" represents an alkyl, aryl or cycloaliphatic group advantageously of no more than carbon atoms. The group of basic catalysts may be represented generically by the formula MOR wherein R' represents R or hydrogen and M is as defined above. The quaternary ammo nium compounds may be represented by the formula (R) NOR"'. Typical compounds are NaOH, KOH, LiOH, NaOCH KOCH LiOCH NaOC H KOC H LiOC ,H r,, NaOC H KOCgHn, LiOC H NaOC H KOCH C,,H NaOC H NaOC H CH NaOCH CH C,,H tetramethylammonium hydroxide, benzyltrimethyl ammonium hydroxide, tetraethylammonium hydroxide, cyclohexyltrimethylammonium hydroxide, phenyltriethylammonium hydroxide, triphenylmethylammonium hydroxide, tetramethylammonium methoxide, tetramethylammonium ethoxide, and the like.

The rate of cyclization depends on the basicity and concentration of the catalyst, and the solvent. For example, the cyclization is completed within 1-2 hours at reflux with methanol, to a few minutes at room temperature in the same solvent in the presence of l to l() mole percent of sodium methoxide.

Although strong bases are the preferred catalysts, moderately strong acids, such as aryl sulfonic acids, e.g. toluenesulfonic acid, benzene sulfonic acid, naphthalene sulfonic acid, etc., also catalyze and complete the cyclization process. In contrast, the presence of strong dehydrating acids, e.g., sulfuric acid, promotes side reactions leading to products other than the desired benzisothiazolinones.

A number of the simpler mercapto starting esters and ester disulfides are available commercially, such as methyl 2-mercaptobenzoate and the corresponding disulfide. Higher esters can be prepared by ester inter- 6 change or alcoholysis to replace the methyl group by other groups. However, since this group is removed and generally discarded in subsequent cyclization, the methyl group is preferred because of its lower weight and availability.

As shown in the prior art, it is possible to prepare mercapto esters having Y groups by starting with anthranilic acid derivatives having the desired Y groups attached and then replacing the amine group with a mercapto group by means ofa diazonium reaction. The ester group can also be introduced by esterifying the anthranilic acid derivative. By this means starting compounds can be prepared having Y groups such as Cl, Br, N0 carboalkoxy (COOR'), alkyl, aryl, cycloalkyl, alkoxy, aryloxy, cycloalkoxy, and the like attached to the aromatic nucleus of the: formula. Preferably there are no more than one -NO or COOR' group present per compound.

Typical mercapto esters that can be used. as starting compounds in the practice of this invention include:

Methyl Z-mercaptobenzoate Phenyl Z-mercaptobenzoate Butyl 2-mercaptobenzoate Cyclohexyl Z-mercaptobenzoate Methyl 5-nitro-2mercaptobenzoate Ethyl 4-nitro-2-mereaptobenzoate Propyl 5-chloro-2-mercaptobenzoate Methyl 3,5-dichloro-2-mercaptobenzoate Methyl 3,5-diethoxy-2-mercaptobenzoate Ethyl 4,6-dimethyl-2-mercaptobenzoate Methyl 4-butyl-2-mercaptobenzoate Methyl 4-benzyl-2-mercaptobenzoate Methyl 4-cyclohexyl-2-mercaptobenzoate Methyl 5-phenyl-2-mercaptobenzoate Methyl 5-phenoxy'2-mercaptobenzoate Diphenyl Z-mercapto-terephthalate Typical sulfenamide compounds that can be used in the cyclization process of this invention include:

N-Benzyl-2-carbomethoxybenzenesulfenamide N-Cyclohexyl-2-carbomethoxybenzenesulfenamide N-Propyl-Z-carbomethoxybenzenesulfenamide N-Butyl-2-carboethoxybenzenesulfenamide N-Octyl-2-carbopropoxybenzenesulfenamide N-Allyl2-carbomethoxybenzenesulfenamide N-2-Hydroxyethyl-2-carbomethoxybenzenesulfena mide N-Phenyl-2-carbomethoxybenzenesulfenamide N-(2-Pyrimidyl)-2-carbomethoxybenzenesulfenamide N-( o-Chlorophenyl )-2-carbophenoxybenzenesulfenamide N- m-Chlorophenyl )-Z-carbodecoxybenzenesulfenamide fenamide N-(p-n-Dodecylphenyl )-2-carbomethoxybenzenesulfenamide N-(Z ,6 -Diethylphenyl)-2-carbomethoxybenzenesulfenamide These 1,2-benzisothiazolin-3-ones may be applied directly or indirectly for the local treatment of dermatophytoses, for example, athletes foot and ringworm of the scalp, also as general or urinary antiseptics.

Various methods ofpracticing the invention are illustrated by the following examples. These examples are intended merely to illustrate the invention and not in any sense to limit the manner in which the invention can be practiced. The parts and percentages recited therein and all through the specification, unless specifically provided otherwise, are by weight. Temperatures are given in degrees Centigrade.

EXAMPLE 1 Typical Preparation of Intermediate Benzenesulfenamides as Illustrated by the Preparation of N-Benzyl-2-carbomethoxybenzenesulfenamide oca SNHCH2C6H5 A solution of bromine (64 g., 0.4 mole) in carbon tetrachloride (200 ml.) is added dropwise with stirring to a solution of methyl 2-mercaptobenzoate (67.4 g., 0.4 mole) in carbon tetrachloride (100 ml.) at 25-30 C. The red solution of the sulfenyl bromide obtained is stirred at room temperature for 1 hour, and added dropwise to a stirred solution of benzylamine (42.9 g., 0.4 mole), triethylamine (60.7 g., 0.6 mole) and carbon tetrachloride (1 liter). The precipitated triethylamine hydrobromide is filtered off and the filtrate evaporated to dryness under vacuum to yield an oil, which is dissolved in methanol (100 ml.) and cooled. Almost pure product (87.9 g., m.p. 58-61 C.) is thus obtained in 80% theoretical yield. An analytical sample (m.p. 61-62.5 C.) is prepared by recrystallization from methanol.

Analysis calculated for C, -,H,,,NO S: C, 65.91; H,

Found: C, 66.15; H, 5.70; N, 5.10; S, 11.49

Other intermediate benzenesulfenamides such as listed above for use in the cyclization process of this invention are prepared using other starting materials and reagents appropriate for giving the desired groups and structures in the intermediate compounds.

EXAMPLE 11 Preparation of 2-Benzyll ,2-benzisothiazolin-3-one A solution of the N-Benzyl2-carbomethoxybenzenesulfenamide prepared in Example I (2.7 g., 0.01 mole) and 0.45 ml. of 20% methanolic tetramethylammonium hydroxide in isopropanol (8 ml.) is refluxed for 10 minutes and then cooled. The crystallized solid is filtered off and dried, giving almdst pure product 1.6 g., m.p. 86-88) in 67% theoretica 'eld. This product has the formula EXAMPLE [11 Preparation of 2-cycloliexyl-l ,2-benzisothiazlin-3-one A solution of sodium hydroxide (0.08 g., 0.002 mole) in ethanol (2 m1.) is added at room temperature to a stirred solution of crude N-cyclohexyl-2-carbomethoxybenzenesulfenamide (5.3 g., 0.02 mole) in ethanol (25 ml.). A mild exothermic reaction occurs which raises the temperature of the solution to ca. 40. The reaction mixture is stirred at ambient temperature for 1 hour, evaporated to dryness, dissolved in chloroform, washed with water, dried (MgSO and evaporated to dryness, giving an oil which solidifies upon standing. This crude product (4.5 g., m.p. 83-86, yield 94% of theory) is purified by one recrystallization from etherhexane to yield the pure compound (3.9 g., m.p. 8688) in 82% yield. (Reported m.p. 8788.)

EXAMPLE l'V Preparation of 2-Propyl-l ,2-benzisothiazolin-3-one A. By Catalytic Cyclization Crude N-propyl-Z-carbomethoxybenzenesulfenamide (28.3 g., 0.125 mole) prepared according to the procedure of Example 1 is heated under reflux with methanolic potassium hydroxide (50 ml. of methanol containing 0.0125 mole of OH) for 3 hours. The mixture is neutralized with the calculated amount of hydrochloric acid, and the crude product is distilled twice to provide the analytical sample, bgp. 126-128 at 0.05 mm.

Analysis Calcd. for C H NOS: C, 62.14; H, 5.74; N.

Found: C, 62.02; H, 7.59; N, 7.09; S, 16.45 The proposed structure is also identified by IR and NMR analysis.

B. By Thermal Decomposition Crude N-Propyl-2-carbometl1oxybenzenesulfenamide is heated to 200 at l to 0.1 mm Hg. Liquid 2- propyl-l,Z-benzisothiazolin-3-one is distilled over and identified by [R and NMR analysis.

EXAMPLE V Preparation of 2-Phenyl-1,2-benzisothiazolin-3-one N-phenyl-2-carbomethoxybenzenesulfenamide (2.6 g., 0.01 mole) is heated under reflux in isopropanol (8 ml.) into which 2.4 mg. (10 mole) of sodium hydride has been added. Upon cooling 2.5 g. of the product crystallizes out and is purified by crystallization from ethanol, and then from acetone. The m.p. is 142-143.5. (Reported m.p. l43-l44.)

EXAMPLE V1 Preparation of 2-Al1yl-l ,Z-benzisothiazolin-3-one Crude N-a1lyl-2-carbomethoxybenzenesulfenamide (23.3 g.) is prepared as in Example land heated under reflux in 30 m1. ofmethanol containing 0.56 g. ofpot'assium hydroxide. The reaction mixture is diluted with water (200 ml.), acidified with concentrated hydrochloric acid (1 ml.), and extracted with carbon tetrachloride. The organic layer is separated, washed with water, dried (MgSO and evaporated to dryness, to yield an oil which is distilled in vacuo. The fraction boiling at l30l37/0.2-0.3 mm. solidifies upon standing and is purified by crystallization from ether-hexane. The pure product melts at 49-50.5. (Reported m.p. 49-50.).

EXAMPLE VII Preparation of 2-( 2-Hydroxyethyl)- l ,2-benzisothiazolin-3-one A solution of crude N-(Z-hydroxyethylJ-Z- carbomethoxybenzenesulfenamide (10.5 g.) (Prepared according to the procedure of Example I.) in methanol (100 ml.) containing 1 ml. of a 40% methanolic solution of benzyltrimethylammonium hydroxide (Triton B) is heated under reflux for 30 minutes. The solution is then evaporated to dryness to give the product which is purified by recrystallization from acetone. The m.p. is ll2l l4; reported m.p. l04l06. The structure is confirmed by IR and NMR spectra.

Example VIll Preparation of 2-(p-Pyrimidyl)-l ,2-benzisothiazolin-3-one To a stirred suspension of N-(2-pyrimidyl)-2- carbomethoxybenzenesulfenamide (2.6 g., 0.01 mole, prepared according to the procedure of Example I) in ethanol (20 ml.), aqueous sodium hydroxide (0.001 mole) is added and the mixture is heated under reflux for 2 hours. The solution obtained is evaporated to dryness, giving a solid. This solid is taken up in water (100 ml.) filtered off, and recrystallized from ethanol to yield pure product, m.p. 237-238, reported m.p. 236. This product has the formula @Qadli EXAMPLE [X The procedure of Example II is repeated a number of times using individually the following intermediates prepared according to the procedure of Example I:

a. N-p-Chlorobenzyl-2-carbomcthoxybenzenesulfenamide b. N-( 2 '.6-Dimethylphenyl )-2-carboethoxybenzencsulfenamidc c. N-(2',4-Dimethylphenyl)-2-carbophenoxybenzenesulfenamide d. N-(p-n-Butylphenyl)-2-carbomethoxybenzenesulfenamide e. N-Benzyl-6-methyl-2-carbomethoxybenzenesulfenamide f. N-Phenyl-S-chloro-2-carbopropoxybenzenesulfenamide g. N-Butyl--methoxy-2-carbocyclohexoxybeno. N-Allyl-2-carbomethoxybenzenesulfenamide p. N-Propargyl-2-carbomethoxybenzenesulfenamide q. N-(4-Hydroxybutyl)-2-carbomethoxybenzenesulfenamide The respective produces are identified as:

a. 2-p-Chlorobenzyll ,2-benzisothiazolin-3-one b. 2-(2,6-Dimethylphenyl)-l,2benzisothiazolin- 3-one c. 2-(2',4'Dimethylphenyl)-l,Z-benzisothiazolin- 3-one d. Z-p-n-Butylphenyl-l ,2-benzisothiazolin-3-one e. 2-Benzyl-7-methyll ,2-benzisothiazolin-3-one f. 2-Phenyl-6-chloro-l ,2-benzisothiazolin-3-one g. 2-Butyl-6-methoxy-l ,Z-benzisothiazolin-3-one h. 2-p-Bromophenyl--butoxy-1,2-benzisothiazolin- 3-one i. 2-(4-Pyridyl)-7-phenyl-l,Z-benzisothiazolin-3-one j. 2-Cyclo-octyl-5 ,7-difluoro-l ,2-benzisothiazolin- 3-one k. 2-Octyl-6-phenoxy-l,2-benzisothiazolin-3-one l. 2-Butoxyethyl-6-(p-methoxy-phenyl)-l,Z-benzisothiazolin-3-one m. Z-Methoxycyclohexyl-l,2-benzisothiazolin-3-one n. 2-Ethoxyphenyl-l ,Z-benzisothiazolin-3-one o. 2-Allyl-l,2-benzisothiazolin-3-one p. 2-Propargyl-l,2-benzisothiazolin-3-one q. 2-(4-Hydroxybutyl)-l ,2-benzisothiazolin-3-one EXAMPLE X Attempted Preparations of Z-Carbomethoxyphenyl sulfenamide:

mide:

COOCH CH OOC S "-NH -'S This structure is confirmed with Infrared and NMR data. The analyses show: C. 54.76; H. 4.25; N, 3.99; 5. 18.35; which values agree closely with the calculated values of C, 55.00; H. 4.33; N, 4.0l; 5, 18.35.

EXAMPLE Xl One part of 2-p-chlorobenzyl-l ,Lbenzisothiazolin- 3-one, 66.5 parts of arachis oil, ll parts of anhydrous lanolin, 17 parts of soft paraffin and 5.5 parts of hard paraffin are thoroughly mixed, giving a mixture suitable for topical applicatio h for therapeutic purposes.

EXAMPLE Xll One part of 2-p-chlorobenzyl-l,Z-benzisothiazolin- 3-one and 99 parts of isopropanol are thoroughly mixed giving a mixture suitable for toptical application for therapeutic purposes.

EXAMPLE Xlll A mixture of 0.5 part of 2-p-chlorobcnzyl-l,Z-benzisothiazolin-3-one, l0 parts of anhydrous citric acid,

4.23 parts of lactose and 0.02 part of sodium diiso' propylnaphthalene sulphonate is granulated with a sufficient quantity of ethanol. The granules are passed through a l6-mesh screen and dried at a temperature not exceeding 60 C. A mixture of 2.85 parts of anhydrous sodium carbonate, 2 parts of anhydrous sodium sulphate and 0.4 part of magnesium stearate is screened through a 20-mesh screen and mixed with the granules. The mixture is compressed between capsuleshaped punches and there are thus obtained pessaries suitable for therapeutic purposes.

EXAMPLE XIV 70 parts of glycerine are added to a mixture of 2.5 parts of micropulverized Z-p-chlorobenzyl-l ,2-benzisothiazolin-3-one, 13.5 parts of water and 14 parts of gelatine. The resultant mixture is warmed to 75 C. with stirring, then poured into moulds lubricated with liquid paraffin. There are thus obtained suppositories suitable for therapeutic purposes.

EXAMPLE XV One part of 2-p-chlorobenzyl-l,2-benzisothiazolin- 3-one is mixed with a mixture of 60 parts of polyethylene glycol 400 and 39 parts of polyethylene glycol 4000, and the mixture is warmed with stirring until it is homogeneous. The mixture is stirred until cool and there is thus obtained an ointment suitable for topical application for therapeutic purposes.

EXAMPLE XVl A mixture of one part of 2-(2,6'-dimethylphenyl)- l,2-benzisothiazolin-B-one, 1 part of a dispersing agent comprising a mixture of disodium methylenedinaphthalene-B-sulphonic acid and sodium naphthalene-B-sulphonic acid, and 80 parts of water is ground in a ball mill to give a dispersion. 9 parts of this dispersion are added to 1,000 parts of water containing 0.15 part of a non-ionic surface active agent comprising an alkyl phenol condensed with ethylene oxide. This mixture is sprayed on oat seedlings which are subsequently inoculated with spores of Erysiphe graml'nis var. avenue and kept in an environment conducive to spore germination and infection. Complete control of the disease is obtained.

EXAMPLE XVll A mixture of 1 part of 2-(2,4'-dimethylphenyl)-l.2- benzisothiazolin-3-one, l part of a dispersion agent comprising a mixture ofdisodium methylencdinaphthalene-B-sulphonic acid and sodium naphthalene-[3- sulphonic acid, and 80 parts of water is ground in a ball mill to give a dispersion. 45 parts of this dispersion are added to L000 parts of water containing 0.15 part of a non-ionic surface active agent comprising an alkyl phenol condensed with ethylene oxide. This mixture is sprayed on tobacco seedlings which are subsequently inoculated with spores of Peronospora tabacina and kept in an environment conducive to spore germination and infection. 95% control of the disease is obtained.

EXAMPLE XVIII A mixture of one part of Z-p-n-butylphenylbenzisothiazolin-3-one, 1 part ofa dispersing agent comprising a mixture of disodium methylene-dinaphthalene-B- sulphonic acid and sodium naphthalene-B-sulphonic acid, and 80 parts of water is ground in a ball mill to give a dispersion. Nine parts of this dispersion are added to 1000 parts of water containing 0.15 part of a non-ionic surface active agent comprising an alkyl phenol condensed with ethylene oxide. This mixture is sprayed on wheat seedlings which are subsequently inoculated with spores of Puccinia tiriricina and kept in an environment conducive to spore germination and infection. Complete control of the disease is obtained.

While certain features of this invention have been described in detail with respect to various embodiments thereof, it will, of course, be apparent that other modifications can be made within the spirit and scope ofthis invention and it is not intended to limit the invention to the exact details shown above except insofar as they are defined in the following claims:

The invention claimed is:

l. The process of preparing a l,2-benzisothiazolin- 3-one of the formula comprising the steps of cyclizing an aromatic sulfenamide of the formula wherein R represents a hydrocarbon radical of not more than 20 carbon atoms, a hydroxyalkyl radical of not more than 8 carbon atoms, halogenated aromatic hydrocarbon radical in which the halogen is attached to an aromatic nucleus therein, or pyrimidyl or pyridyl radical in which said radical is attached to the nitrogen of the formula through a valency on a carbon atom of its nuclear ring; and R represents a hydrocarbon radical of not more than 20 carbon atoms, the aliphatic portions of which are saturated; said cyclization being effected at a temperature of 0-l00C. in the presence of an alkaline material having no more than 10 carbon atoms therein and selected from the class consisting of alkali metal hydroxide, alkoxidc, aryloxide. cycloalkoxide, primary, secondary and tertiary amines. and quaternary ammonium hydroxide.

2. The process of claim 1 in which said cyclization is effected at approximately room temperature.

3. The process of claim 1 in which said cyclization is effected at a temperature in the range of 20 to l00 C.

4. The process of claim 3 in which said alkaline material is a primary, secondary or tertiary amine.

5. The process of claim 3 in which said alkaline material is a quaternary ammonium hydroxide.

6. The process of claim 3 in which said alkaline material is an alkali metal alkoxide of the formula MOR" wherein M is an alkali metal and R represents an alkyl, aryl or cycloalkyl radical of no more than 10 carbon atoms.

7. The process of claim 3 in which said aromatic sulfenamide is N-benzyl-2-carbomethoxybenzenesulfenamide.

8. The process of claim 3 in which. said aromatic sulfenamide is N-cyclohexyl2-carbomethoxybenzenesulfenamide.

9. The process of claim 3 in which said aromatic sul- O fenamide is N-propyl-Z-carbomethoxybenzenesulfenai mide. c

10. The process of claim 3 in which said aromatic sulfenamide is N-phenyl-Z-carbomethoxybenzenesuIfena- H mide.

11. The process of claim 3 in which said aromatic sulfenamide is N-allyl-Z-carbomethoxybenzenesulfenafollowed by amidation of the resultant chlorinated or mide. brominated product with RNH- wherein R and R are 12. The process of claim 3 in which said aromatic sulas defined in claim 1, and the cyclization of the resul fenamide is N-(Z-hydroxyethyl)-2-carbomcthoxybentant aromatic sulfenamide to the 1,2-benzisothiazolinzenesulfenamide. 3-one is effected as in claim 1 without isolation of any 13. The process of chlorination or bromination of a of the intermediate compounds. Z-mercaptobenzoic acid of the formula 

2. The process of claim 1 in which said cyclization is effected at approximately room temperature.
 3. The process of claim 1 in which said cyclization is effected at a temperature in the range of 20* to 100* C.
 4. The process of claim 3 in which said alkaline material is a primary, secondary or tertiary amine.
 5. The process of claim 3 in which said alkaline material is a quaternary ammonium hydroxide.
 6. The process of claim 3 in which said alkaline material is an alkali metal alkoxide of the formula MOR'''' wherein M is an alkali metal and R'''' represents an alkyl, aryl or cycloalkyl radical of no more than 10 carbon atoms.
 7. The process of claim 3 in which said aromatic sulfenamide is N-benzyl-2-carbomethoxybenzenesulfenamide.
 8. The process of claim 3 in which said aromatic sulfenamide is N-cyclohexyl-2-carbomethoxybenzenesulfenamide.
 9. The process of claim 3 in which said aromatic sulfenamide is N-propyl-2-carbomethoxybenzenesulfenamide.
 10. The process of claim 3 in which said aromatic sulfenamide is N-phenyl-2-carbomethoxybenzenesulfenamide.
 11. The process of claim 3 in which said aromatic sulfenamide is N-allyl-2-carbomethoxybenzenesulfenamide.
 12. The process of claim 3 in which said aromatic sulfenamide is N-(2-hydroxyethyl)-2-carbomethoxybenzenesulfenamide.
 13. The process of chlorination or bromination of a 2-mercaptobenzoic acid of the formula 